Ammonium metavanadate (NH4VO3): a highly efficient and eco-friendly catalyst for one-pot synthesis of pyridines and 1,4-dihydropyridines

In this study, we reported the ammonium metavanadate (NH4VO3) as an efficient, cost-effective, and mild catalyst for the synthesis of substituted pyridines via a one-pot pseudo four-component reaction. Furthermore, we investigated Hantzsch 1,4-dihydropyridines (1,4-DHPs) synthesis and oxidation of 1,4-DHPs to their corresponding pyridines. The present approach offers a rapid methodology for accessing various pyridines with broad functional group tolerance and good yields using NH4VO3 catalyst as a green catalyst.


Results and discussion
Regarding the fact that the one-pot approach to the synthesis of substituted pyridines through Hantzsch synthesis is hardly carried out and there are only a few literatures reported in this field. Hence, the efficiency of ammonium metavanadate (NH 4 VO 3 ) was investigated in the one-pot synthesis of pyridine derivatives. In an initial attempt, the condensation of 4-chlorobenaldehyde (1.0 mmol) with ethyl acetoacetate (2.0 mmol) and ammonium acetate (2.0 mmol) as a model reaction (Fig. 3) was examined in the presence of different catalytic amounts of NH 4 VO 3 in acetic acid for the one-pot synthesis of pyridine derivatives. Surprisingly, when NH 4 VO 3 was used as the catalyst in acetic acid under reflux conditions, the reaction went to completion in 10 min and 96% of the pyridine (product 8f.) was isolated as the desired product.
To optimize the amount of catalyst and reaction conditions for the one-pot synthesis of pyridines, the model reaction was examined in acetic acid ( Table 1). As shown in Table 1, the best results were achieved when the reaction was carried out in the presence of 117.0 mg of NH 4 VO 3 as the catalyst in acetic acid under reflux conditions (entry 1, Table 1). Increasing the amount of catalyst (117.0-120.0 mg) did not improve the yield of the desired product (entries 1-5, Table 1). In the absence of NH 4 VO 3 catalyst, the reaction was not successful (entry 11, Table 1). www.nature.com/scientificreports/ After optimizing the reaction conditions, to explore the scope of the reaction, a series of pyridine derivatives were synthesized by various aldehydes including both electron-donating and electron-withdrawing substituents ( Table 7). All the aldehydes with both electron-withdrawing groups and electron-donating groups reacted very well, giving high yields of the desired products in short reaction times. Based on the results, we propose a plausible mechanism for the one-pot synthesis of pyridines (Fig. 4). This mechanistic pathway includes a combination of the Hantzsch synthesis and the subsequent oxidation step. First, the ammonium (NH 4 + ) group in the structure of NH 4 VO 3 activates the carbonyl functional groups of aldehyde and ethyl acetoacetate by hydrogen bonding. Therefore, it increases the carbonyl activity to Knoevenagel condensation with enol form of ethyl acetoacetate to give the corresponding Knoevenagel intermediate (I). In the next step, the reaction of the second molecule of ethyl acetoacetate with ammonium acetate gives the imine intermediate (II). The Michael addition of I with enamine form of II occurs to form intermediate III, which is activated through hydrogen bonding from NH 4 VO 3 to facilitate cyclization and elimination of water, affording the desired 1,4-DHP derivatives. In continue, acetic acid using NH 4 VO 3 as a catalyst is converted into acetate ion which is leading to an acid-base reaction with 1,4-DHPs. In the following, the negative charge of nitrogen of intermediate (IV) binds with the vacant "d" orbital of transition metal vanadium to achieve the stable oxidation state of vanadium. The last step might be progressed through unusual hydride transfer and H 2 releasing from (V). For proving this opinion, the reaction was evaluated under a nitrogen atmosphere (entry 2, Table 1). The results show that the oxidation reaction progressed in an atmosphere of nitrogen similar to the air or oxygen atmosphere condition (entries 1-3, Table 1). Due to electron-donating from the nitrogen lone pairs into the anti-bonding orbital of C-H (s * C-H orbital), the C-H bond is easily broken by reaction with a proton to afford molecular hydrogen. This phenomenon has been known as the anomeric effect.
Although there are a few literatures that reported on the direct approach for the one-pot synthesis of pyridines, this method is superior to the earlier methods in terms of yields, reaction time, and mild reaction conditions (Table 2).
To further confirm the possible mechanism, we also examined the efficiency of NH 4 VO 3 as a catalyst for the one-pot synthesis of 1,4-DHPs. To optimize the reaction conditions. The condensation of 4-chlorobenaldehyde (1.0 mmol) with ethyl acetoacetate (2.0 mmol) and ammonium acetate (2.0 mmol) as a model reaction (Fig. 5) was chosen and the effect of different catalytic amounts of NH 4 VO 3 in a wide variety of solvents and under reflux condition were investigated (Table 3).  www.nature.com/scientificreports/ In the absence of NH 4 VO 3 as the catalyst, the reaction proceeded slowly with a low yield (entry 16, Table 3). As seen in Table 3 (entries 7-12) using 15.0-23.0 mg of the catalyst (NH 4 VO 3 ) showed higher activity for the synthesis of 1,4-DHPs. However, when the amount of catalyst increased to 18.0-23.0 mg (entries 10-12, Table 3) the yield of the desired product (93%) did not improve. Among the investigated solvents, ethanol is the best choice with its short reaction time, high yield, cheapness, and being environmentally friendly for this reaction. According to the results in Tables (1,3), it is obvious that in the absence of acetic acid and using other solvents the  www.nature.com/scientificreports/ 1,4-DHPs form as the desired products. After optimizing the reaction conditions, the effect of substitution on the aldehydes has also been studied. As shown in Table 7 all the aromatic aldehydes with both electron-withdrawing groups and electron-donating groups reacted very well, giving high yields of the desired products. As expected substituted aldehydes with electron-withdrawing groups require a shorter reaction time in comparison to those with electron-donating groups.   www.nature.com/scientificreports/ Moreover, the catalytic activity of the NH 4 VO 3 for the synthesis of 1,4-DHPs was compared to the other reported catalysts in Table 4.
As revealed in Table 5 (entries 1-8), the nature of the solvent is an important factor in the oxidation of 1,4-DHPs to the corresponding pyridines. The effect of the solvent in the oxidation reaction, in dichloromethane, ethanol, chloroform, H 2 O, acetonitrile, formic acid, and tetrahydrofuran was investigated; no oxidation occurred in these solvents. While by addition of acetic acid as the solvent to the reaction mixture, the yield of the desired product reached 96% under reflux conditions (entry 8, Table 5), this observation suggests that acetic acid is  www.nature.com/scientificreports/ essential for the oxidation reaction. Additionally, the model substrate converts into the corresponding pyridine in acetic acid at room temperature (entry 9, Table 5). The model substrate was treated with 58.0-180.0 mg of NH 4 VO 3 in the presence of acetic acid under reflux conditions (entries 10-16, Table 5). The satisfactory yield of the desired product can be obtained with 117.0 mg of NH 4 VO 3 (entry 8, Table 5). The experiment was conducted in the oxygen, nitrogen, and air atmosphere (entries 8-11, Table 5), the oxidation reaction progressed in the nitrogen atmosphere the same as in normal reaction conditions using air or oxygen atmosphere. Under the optimized reaction conditions, the catalytic performance of NH 4 VO 3 was further evaluated for the oxidation reaction of various 1,4-DHPs containing electron-withdrawing and donating substituents ( Table 7). The Hantzsch 1,4-DHPs including a variety of substituents were converted to the corresponding pyridines in excellent yield (Table 7). Based on the results for the oxidation of 1,4-DHPs by other catalysts reported previously (Table 6), the NH 4 VO 3 can act as a highly efficient heterogeneous catalyst in oxidation reaction through a facile method (Table 7).

Conclusion
In conclusion, a novel and convenient approach for the one-pot synthesis of pyridine derivatives through the one-pot pseudo four-component reaction, and oxidation of 1,4-DHPs by using NH 4 VO 3 as the catalyst has been developed. NH 4 VO 3 is an efficient, commercially available, inexpensive, and eco-friendly catalyst for these reactions. These methods involve several remarkable advantages, such as simple procedure, mild reaction conditions, short reaction times, high yields, and ease of product isolation.

Data availability
All data generated or analyzed during this study are included in this published article and its supplementary information file. The data is also available through request from corresponding author.